Medicinal forms of phospholipid preparations and methods for their preparation

ABSTRACT

A method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier substance or additive, granulating the resultant mixture, and encapsulating the resultant product, for example after grinding with a pharmaceutically acceptable carrier substance or additive. Products obtained by this method form a further aspect of the invention, and are useful in the treatment or prevention of diseases associated with liver disorders.

The invention relates to the area of pharmaceutics and concerns the production technology of encapsulated medicinal form of a phospholipid preparation, in particular that available as “Phosphogliv” for treatment and preventive measures of acute and chronic liver diseases, lipid exchange disorder and/or restoration of liver function after intoxication. The above-mentioned preparation contains vegetative phospholipids, glycyrrhizic acid or its salts and auxiliary substances.

It is known that liver pathological processes of various diseases are accompanied by the structural and functional damage of membrane hepatocyte systems. Damage to membranes is caused by lipid stratum disorder due to the involvement of lipids in the processes of peroxidation and endogenous phospholipase activity. Any change in the physicochemical properties of lipids can result in structural damage to lipid biomembrane matrix and loss of their barrier function that is accompanied by inactivation of membrane enzyme systems.

It has been shown in numerous research studies (including some conducted by the Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences) that the most effective phospholipids for use in the restoration of the damaged hepatocyte membranes are phospholipids derived from vegetative material. Such vegetative phospholipids incorporate essential fatty acids (linoleic and linolenic acid), which make them more liquid than usual membrane phosphatidylcholine. This seems to allow them to play the role of “membrane glue”, capable to repair defects of the damaged cellular membranes more effectively. The mechanism of action of vegetative phospholipids appears to be due to the inclusion of polyunsaturated phosphatidylcholine into membranes and it is capable of restoring the structure and function of the damaged cells.

Therefore the development of effective medicinal forms which incorporate phospholipids remains important.

There are a number of preparations which include phospholipids, which are produced in capsules, dragee or pills, and also injectable forms.

“Essentiale” is one of such preparations which has been applied in practical public health services more than 40 years to restore liver functions. A more recent preparation is sold as “Essentiale H” (Natterman Co. Germany) and contains a mixture of phospholipids and unsaturated fatty acids.

A key component of the phospholipids used in the preparations is phosphatidylcholine and so this should be present at high concentrations. At present, only a viscous syrupy form is available for use in the production of encapsulated forms of phospholipid preparations with high contents of phosphatidylcholine.

The above-mentioned known oral forms of preparations “Essentiale” and “Essentiale H” represent the capsules containing the syrupy substance. This mass contains moisture. considerably reducing the shelf life or storage ability of the preparations and increasing their toxicity due to formation of lysophosphatidylcholine, which is a product of phosphatidylcholine oxidation. There is also another known phospholipid preparation,

“Phosphogliv”, which is used for the treatment and prevention of liver disease. It contains vegetative phospholipids with a high phosphatidylcholine content (75-98%), as well as glycyrrhizic acid, salts and additional ingredients. Glycyrrhizic acid and its salt, can act as an emulsifier, but also possesses hepatoprotector, anti-inflammatory, antiallergic and anti-viral properties, besides having a mild detergent effect.

There are however, problems associated with the production of suitable medicinal forms of these phospholipid preparations.

In particular, lactose and aerosil have previously been included in the formulations in order to produce successfully granulated forms. However, the obtained tablet mass including phospholipid and salt of glycyrrhizic acid is inappropriate for formation of tablets. Tablets turn out non-uniform and chipped.

In addition, the storage time for aerosil is limited (no more than 6 months). It has a high toxicity and may constitute a health hazard during the manufacturing process.

On the other hand, the usage of lactose hinders the preparation of capsules and the resultant granules are not compatible with automatic capsule filling machines. As a result, the filling is non-uniform, the mass is cloddy and the machine finally becomes clogged.

The applicants have found a way by which certain problems in the production of encapsulated medicinal forms of the phospholipid compositions and in particular those sold as “Phosphogliv”, can be reduced or eliminated.

According to the present invention, there is provided a method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable carrier substances or additives, granulating the resultant mixture, and encapsulating the resultant product.

In particular, the method is used to produce compositions in which the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof is not greater than 4:1, suitably in the range of from 0.5:1 to 4:1, for example at about 2:1. Suitably the encapsulated material comprises from 2-80% w/w total phospholipid and glycyrrhizic acid or pharmaceutically acceptable salt thereof.

In a particular embodiment the phospholipid used is obtained from a vegetative source such as soybean extract, which suitably comprises from 75-98% w/w of phosphatidylcholine.

The organic solvent (or spirit) used in the method is suitably an organic solvent in which the phospholipid is soluble. Preferably the organic solvent is a pharmaceutically acceptable organic solvent such as ethanol.

Suitable pharmaceutically acceptable salts of glycyrrhizic acid are alkaline or alkaline earth metal salts such as sodium, potassium, calcium and magnesium salts. A particularly suitable salt of glycyrrhizic acid is the trisodium (trinatrium) salt.

The granulation step is suitably effected using an initial damp granulation procedure, followed by a dry granulation procedure, as would be understood in the art. In particular, in the method, the product of the granulation step is powdered with a pharmaceutically acceptable carrier substance or additive, before encapsulation.

As used herein, the expression “pharmaceutically acceptable carrier substance or additive” includes materials in particular solid materials which are well known in the formulation art, for example, as carriers, diluents, preservatives, dispersants, colouring, sweetening, flavouring agents etc, or mixtures thereof. They include for example calcium carbonate, calcium stearate, talc, sodium carbonate, calcium phosphate, microcrystalline cellulose or mixtures of one or more of these.

Suitably they do not include either lactose or aerosil.

They may be added together with the glycyrrhizic acid or a pharmaceutically acceptable salt thereof, where particularly suitable pharmaceutically acceptable carrier substances or additives include microcrystalline cellulose, calcium stearate and calcium carbonate or mixtures of one or more of these.

Alternatively, as mentioned above, the product of the granulation step may be ground or powdered together with a suitable pharmaceutically acceptable carrier substance or additive. In an embodiment the pharmaceutically acceptable carrier substance or additive may be calcium carbonate, calcium stearate, talc or a mixture thereof.

Encapsulation of the resultant product is carried out in a conventional manner, for example using gelatinous or other capsule materials. Preparations prepared by the method described above form a further aspect of the invention. They may be used in particular for the preparation for the treatment and prevention of liver diseases, lipid exchange disorder, as well as the restoration of liver function after intoxication. The obtained capsulated preparation preserves physicochemical properties, does not become compressed and does not conglutinate for a long period of time (storage over 4 years has been demonstrated).

The invention will now be particularly described by way of example.

EXAMPLE 1.

Phospholipid (PL) (0.52 Kg) from soya with a content of phosphatidylcholine (PC) of 80% was dissolved in ethanol (0.52 kg; 0.65 litre) over a period of 3-4 hours. Microcrystalline cellulose (1.28 Kg), the trinatrium salt of glycyrrhizic acid (GA) (0.28 Kg) and calcium carbonate (0.71 Kg) were loaded into the mixer. The organic solution of phospholipid was added to the resultant mixture obtained giving a ratio of PL:GA of 2:1. The contents of the mixer were mixed for three minutes and thereafter subjected to a damp granulation procedure in which the diameter of apertures was 3.0 mm. The damp granulated material was dried for 3-4 hours and then subjected to a dry granulation procedure in which it was passed through apertures with diameter of 1.2 mm. The obtained granulated material (2.80-2.85 kg) was ground (powdered) together with calcium carbonate (0.71 kg), talc (0.078 kg) and calcium stearate (0.024 kg) for no more than 10 minutes (total contents of PL and GA about 22%). This mass was encapsulated in gelatinous (or other) capsules.

The preparation was found to be stable after four years. The described method therefore provides a stable, highly effective preparation which can be used in clinical practice for complex treatment of various diseases associated with liver function disorders. 

1. A method for producing an encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof, said method comprising mixing a solution of phospholipid in an organic solvent with glycyrrhizic acid or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier substance or additive, granulating the resultant mixture, and encapsulating the resultant product.
 2. A method according to claim 1 wherein the ratio of phospholipid to glycyrrhizic acid or pharmaceutically acceptable salt thereof is not greater than 4:1.
 3. A method according to claim 1 wherein the total content of phospholipid and glycyrrhizic acid or pharmaceutically acceptable salt in the encapsulated material is from 2-80% w/w of the encapsulated material.
 4. A method according to claim 1 wherein the phospholipid used is in the form of a vegetative extract.
 5. A method according to claim 4 wherein the vegetative extract comprises from 75-98% of phosphatidylcholine.
 6. A method according to claim 1 wherein the granulation is effected using an initial damp granulation procedure, followed by a dry granulation procedure.
 7. A method according to claim 1 wherein the product of the granulation step is powdered with a pharmaceutically acceptable carrier substance or additive before encapsulation.
 8. A method according to claim 7 wherein the pharmaceutically acceptable carrier substance or additive is calcium carbonate, calcium stearate, talc or a mixture thereof.
 9. A method according to claim 1 wherein a pharmaceutically acceptable carrier substance or additive which comprises microcrystalline cellulose, calcium stearate and/or calcium carbonate is added with the glycyrrhizic acid or a pharmaceutically acceptable salt thereof.
 10. An encapsulated medicinal form of a combination of phospholipid and glycyrrhizic acid or a pharmaceutically acceptable salt thereof obtainable by a method according to claim
 1. 